[Research Articles] Enhanced SARS-CoV-2 neutralization by dimeric IgA
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), primarily infects cells at mucosal surfaces. Serum neutralizing antibody responses are variable and generally low in individuals that suffer mild forms of COVID-19. Although potent immunoglobulin G (IgG) antibodies can neutralize the virus, less is known about secretory antibodies such as IgA that might affect the initial viral spread and transmissibility from the mucosa. Here, we characterize the IgA response to SARS-CoV-2 in a cohort of 149 convalescent individuals after diagnosis with COVID-19. IgA re...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Wang, Z., Lorenzi, J. C. C., Muecksch, F., Finkin, S., Viant, C., Gaebler, C., Cipolla, M., Hoffman, H.-H., Oliveira, T. Y., Oren, D. A., Ramos, V., Nogueira, L., Michailidis, E., Robbiani, D. F., Gazumyan, A., Rice, C. M., Hatziioannou, T., Bieniasz, P. Tags: Research Articles Source Type: research
[Perspectives] Does protein aggregation drive postmitotic tissue degeneration?
Pharmacological evidence, from clinical trials where patients with systemic amyloid diseases are treated with disease-modifying therapies, supports the notion that protein aggregation drives tissue degeneration in these disorders. The protein aggregate structures driving tissue pathology and the commonalities in etiology between these diseases and Alzheimer’s disease are under investigation. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Kelly, J. W. Tags: Perspectives Source Type: research
[Research Articles] The cortical origin and initial spread of medial temporal tauopathy in Alzheimers disease assessed with positron emission tomography
Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer’s disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Sanchez, J. S., Becker, J. A., Jacobs, H. I. L., Hanseeuw, B. J., Jiang, S., Schultz, A. P., Properzi, M. J., Katz, S. R., Beiser, A., Satizabal, C. L., ODonnell, A., DeCarli, C., Killiany, R., El Fakhri, G., Normandin, M. D., Gomez-Isla, T., Quiroz, Y. T Tags: Research Articles Source Type: research
[Research Articles] Characterization of ascites- and tumor-infiltrating {gamma}{delta} T cells reveals distinct repertoires and a beneficial role in ovarian cancer
The role of T cells in antitumor immunity has been under investigation for the past two decades, but little is known about their contribution to clinical outcomes in patients. Here, we set out to define the clonotypic, phenotypic, and functional features of T cells in peripheral blood, ascites, and metastatic tumor tissue from patients with advanced epithelial ovarian cancer. T cell receptor (TCR) sequencing of the chain revealed that tumor-infiltrating T cells have a unique and skewed repertoire with high TCR diversity and low clonality. In contrast, ascites-derived T cells presented a lower TCR diversity and higher clona...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Foord, E., Arruda, L. C. M., Gaballa, A., Klynning, C., Uhlin, M. Tags: Research Articles Source Type: research
[Research Articles] ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma
Angiotensin converting enzyme 2 (ACE2) is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) receptor pathway. Here, we report that higher ACE2 expression correlates with better overall survival in patients with clear cell renal cell carcinoma (ccRCC). Moreover, ACE2 has inhibitory effects on tumor proliferation in ccRCC in vitro and in preclinical animal models of ccRCC. We further show that Ang-(1-7), a heptapeptide generated by ACE2, is the likely mediator of this effect. Vascular endothelial growth factor receptor–ty...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Khanna, P., Soh, H. J., Chen, C.-H., Saxena, R., Amin, S., Naughton, M., Joslin, P. N., Moore, A., Bakouny, Z., OCallaghan, C., Catalano, P., Signoretti, S., McKay, R., Choueiri, T. K., Bhasin, M., Walther, T., Bhatt, R. S. Tags: Research Articles Source Type: research
[Research Articles] Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption
Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 5...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Gondim, M. V. P., Sherrill-Mix, S., Bibollet-Ruche, F., Russell, R. M., Trimboli, S., Smith, A. G., Li, Y., Liu, W., Avitto, A. N., DeVoto, J. C., Connell, J., Fenton-May, A. E., Pellegrino, P., Williams, I., Papasavvas, E., Lorenzi, J. C. C., Salantes, D Tags: Research Articles Source Type: research
[Research Articles] Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth
Inflammation contributes to nearly 4 million global premature births annually. Here, we used a mouse model of intrauterine inflammation to test clinically used formulations, as well as engineered nanoformulations, for the prevention of preterm birth (PTB). We observed that neither systemic 17a-hydroxyprogesterone caproate (Makena) nor vaginal progesterone gel (Crinone) was sufficient to prevent inflammation-induced PTB, consistent with recent clinical trial failures. However, we found that vaginal delivery of mucoinert nanosuspensions of histone deacetylase (HDAC) inhibitors, in some cases with the addition of progesterone...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Zierden, H. C., Ortiz, J. I., DeLong, K., Yu, J., Li, G., Dimitrion, P., Bensouda, S., Laney, V., Bailey, A., Anders, N. M., Scardina, M., Mahendroo, M., Mesiano, S., Burd, I., Wagner, G., Hanes, J., Ensign, L. M. Tags: Research Articles Source Type: research
[Research Resources] Measurement of leukocyte trafficking kinetics in macaques by serial intravascular staining
Leukocyte trafficking enables detection of pathogens, immune responses, and immune memory. Dysregulation of leukocyte trafficking is often found in disease, highlighting its important role in homeostasis and the immune response. Whereas some of the molecular mechanisms mediating leukocyte trafficking are understood, little is known about the regulation of trafficking, including trafficking kinetics and its impact on immune homeostasis. We developed a method of serial intravascular staining (SIVS) to measure trafficking kinetics in nonhuman primates using infusions of fluorescently labeled antibodies to label circulating le...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Potter, E. L., Gideon, H. P., Tkachev, V., Fabozzi, G., Chassiakos, A., Petrovas, C., Darrah, P. A., Lin, P. L., Foulds, K. E., Kean, L. S., Flynn, J. L., Roederer, M. Tags: Research Resources Source Type: research
[Research Articles] Targeting cartilage EGFR pathway for osteoarthritis treatment
Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondropro...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Wei, Y., Luo, L., Gui, T., Yu, F., Yan, L., Yao, L., Zhong, L., Yu, W., Han, B., Patel, J. M., Liu, J. F., Beier, F., Levin, L. S., Nelson, C., Shao, Z., Han, L., Mauck, R. L., Tsourkas, A., Ahn, J., Cheng, Z., Qin, L. Tags: Research Articles Source Type: research
[Research Articles] The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer
Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopula...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Vollmer, T., Schlickeiser, S., Amini, L., Schulenberg, S., Wendering, D. J., Banday, V., Jurisch, A., Noster, R., Kunkel, D., Brindle, N. R., Savidis, I., Akyüz, L., Hecht, J., Stervbo, U., Roch, T., Babel, N., Reinke, P., Winqvist, O., Sherif, A. Tags: Research Articles Source Type: research
[Editors' Choice] Probing the entire vascular system
Microscopic endovascular probes that navigate by blood flow and an external magnetic field may increase the capabilities of vascular catheterization. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Kanakry, C. G. Tags: Editors ' Choice Source Type: research
[Editors' Choice] A QuICR test to diagnose Parkinsons disease
Refined conditions permit rapid detection of proteopathic α-synuclein seeds in cerebrospinal fluid from patients with Parkinson’s disease. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Davis, A. A. Tags: Editors ' Choice Source Type: research
[Editors' Choice] In aged hosts, T cells turn traitorous
Multimodal profiling of the aging immune system has identified highly abundant age–associated CD8+ T cells that home to organs and drive inflammation. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Billi, A. C. Tags: Editors ' Choice Source Type: research
[Research Articles] Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity
More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney–specific expression quantitative trait analysis and identified that the expression of beta-mannosidase (MANBA) was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function codi...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Gu, X., Yang, H., Sheng, X., Ko, Y.-A., Qiu, C., Park, J., Huang, S., Kember, R., Judy, R. L., Park, J., Damrauer, S. M., Nadkarni, G., Loos, R. J. F., My, V. T. H., Chaudhary, K., Bottinger, E. P., Paranjpe, I., Saha, A., Brown, C., Akilesh, S., Hung, A. Tags: Research Articles Source Type: research
[Reviews] The microbiota in pneumonia: From protection to predisposition
Mucosal surfaces of the upper respiratory tract and gut are physiologically colonized with their own collection of microbes, the microbiota. The normal upper respiratory tract and gut microbiota protects against pneumonia by impeding colonization by potentially pathogenic bacteria and by regulating immune responses. However, antimicrobial therapy and critical care procedures perturb the microbiota, thus compromising its function and predisposing to lung infections (pneumonia). Interindividual variations and age-related alterations in the microbiota also affect vulnerability to pneumonia. We discuss how the healthy microbio...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Thibeault, C., Suttorp, N., Opitz, B. Tags: Reviews Source Type: research
